Adverse drug reactions occur during the drug development process and post-marketing of the prescribe-based medicine. They are responsible for the termination of approximately 20% of investigational new drugs in the pharmaceutical pipeline. About 1% of marketed drugs is withdrawn or restricted post-marketing due to safety-related issues.
During 1994, adverse drug reactions affected over 2 million people in the United States, resulting in over 100,000 deaths (Lazarou et al., JAMA 1998).
In 2002, adverse drug reactions accounted for 6.5% of hospital admissions and 0.15% of subsequent deaths in the United Kingdom (Pirmohamed et al., BMJ 2004).
Cutaneous adverse drug reactions are among the most common adverse drug reactions and may caused by immune or non-immune mechanisms. The severities of cutaneous reactions were graded according to Division of AIDs table for grading the severities of adverse events NIAID/NIH. Briefly, grade 1: localized macular rash; grade 2: diffuse macular, maculopapular or morbilliform rash or target lesions; grade 3: diffuse macular, maculopapular or morbilliform rash with vesicle or limited number of bullae or superficial ulceration of mucous membrane limited to one site; and grade 4: extensive or generalized bullous lesions or Stevens-Johnson syndrome (SJS) or ulceration of mucous membrane involving two or more distinct mucosal sites or toxic epidermal necrolysis (TEN). (www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/Safety/DAIDSAEGradingTable.pdf)
Risk factors for the development of cutaneous adverse drug reaction may be related to the host factors (eg. certain HLA alleles), the drug and its metabolites (e.g. its reactivity), and underlying conditions (e.g. viral infections). Antibiotics, nonsteroidal anti-inflammation agents, anticonvulsant drugs (Raviglione et al., Drug Saf 1990), allopurinol (Hung et al., Proc Natl Acad Sci USA 2005), antiretroviral agents, particularly abacavir (Abel et al., N Engl J Med 2008) and nevirapine (Kiertiburanakul et al., Curr HIV res 2008), are among the most common causative agents.
Pharmacognomics is the study of biomarkers variations such as genetic variation, RNA variations, protein variations or combination of these variation in the response to medications. The development of pharmacogenomics has implied that the susceptibility to adverse drug reactions is associated with genetic variants. A successful example of the application of pharmacogenomic study to prevent hypersensitivity syndromes is genotyping of HLA-B*5701 before prescribing abacavir in whites. Abacavir is a potent HIV-1 nucleoside analogue reverse transcriptase inhibitor which is complicated by a potentially life threatening hypersensitivity syndrome in about 5% of cases. These reactions are characterized by skin rash, gastrointestinal and respiratory manifestations and can occasionally be fatal, particularly on drug rechallenge. Prospective screening for HLA-B*5701 decreased abacavir hypersensitivity reaction incidence in mix French population from 12% before screening to 0% after screening, and the rate of unwarranted interruptions of abacavir therapy decreased from 10.2% to 0.73%. (Zucman et al., J Acquir Immune Defic Syndr 2007)
Human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) is a significant health problem. By the end of year 2006, 32.2 million individuals were infected and living with HIV worldwide. In 2006 alone, 2.5 million new HIV infection with 2.1 million HIV-related deaths or 5,760 people deaths daily occurs, an estimated 32 million people have died from AIDS since the beginning of the pandemic. Approximately 95% of infected patients living in developing countries especially in Africa, Asian and South America. (UNAID/WHO, 2007)
For Thailand, based on an expert Thais working group estimated 1,109,000 people were infected with HIV, 600,600 anticipated deaths, 508,300 people living with HIV that required continuing care and treatment and 17,000 new cases for 2006 (www.epid.moph.go.th). While the incidence and mortality keeps reducing in Thailand, the delivery of appropriate cares of those who infected prolong patient' life and increase the quality of life.
High Active Antiretroviral Therapy (HAART), the combination of at least three antiretroviral agents comprising at least two NRTIs (Nucleoside Reverse Transcriptase Inhibitors) in combination with at least 1 NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitor) or 1-2 PI (Protease Inhibitor) taken concurrently, represents the current standard of care with antiretroviral therapy. The goal of HAART is to suppress HIV replication to a level below the limit of detection by viral load assays and dramatically improve the patient immune function that results in reduced HIV-related morbidity and mortality and improve quality of life. (aidinfo.nih.gov/ContentFiles/AdultandAldolescentGL.pdf)
Thailand's National Access to Antiretroviral Program for People living with HIV/AIDS (NAPHA) and The Universal health care policy of Thailand were implemented nationwide of antiretroviral therapy to different levels of the public health system increasing dramatically with the number of patients who receiving antiretroviral drug especially GPO-VIR, the fixed-dose combination of stavudine, lamivudine and nevirapine, produced by the Government Pharmaceutical Organization (GPO). GPO-VIR can be taken only 2 tablets per day with the affordably prices making it has been recommended as the first line drug in Thailand.
Non-Nucleoside Reverse Transcriptase Inhibitors comprising nevirapine (NVP), efavirenz (EFV) and dilavirdine (DLV) bind directly to reverse transcriptase enzyme, the binding stops the ability of the reverse transcriptase in replication process. Cutaneous adverse drug reaction is a common side effect of all three NNRTIs. Efavirenz and nevirapine has been recommended as the first line drug in Thailand 2006/2007 because of its effectiveness, easy to administrate with good adherence, excellent food compatibility with affordable prices. Efavirenz has not been made available in combination pill format, patient has to take 7-8 pills per day compare to fixed combination pill consisted of nevirapine as a backbone. EFV is teratogenic and contraindicated in pregnancy, Currently Dilavirdine is not available in majority of developing countries.
EFV is a good alternative for NVP, when hypersensitivity or hepatitis develop in patients who took NVP, The common side effects of EFV included but not limited to drug rash, hepatitis. Both of these side effects had been found less frequent than NVP at rate of 11% and 9% respectively. Central nervous system side effects are more pronounced with EFV, the symptoms include dizziness, vivid dream confusion, suicidal idea, all of these CNS side effects are usually resolved spontaneously after 2 weeks of drug intake (Lee et al., Int Conf AIDS. 2004).
Nevirapine can be used as a single dose intervention peripartum for the prevention of mother-to-child transmission of HIV. It represents an attractive option for patients who must take antiretroviral medications and who prefer a protease inhibitor-sparing regimen as drug resistance regimen. Although antiretroviral therapy is known for its effective treatment, the adverse reaction of drugs is the cause of concern for prescription of NVP. In HIV patients with nevirapine treatment, between 16%-48% of patients reported rash. Second to rash development is hepatitis that can be found in 7-15.6% including fever, nausea, vomiting and dizziness. Furthermore 0.5%4% of patients eventually developed Stevens-Johnson syndrome (SJS) or Toxic epidermal Necrolysis.
The mechanism of nevirapine-induced skin rash is unknown. Some clinical features or characteristics that were associated with nevirapine-induced skin rash had been described such as female gender, low body weight, pretreatment with antiretroviral drugs prior to the nevirapine treatment, a higher level of the number of CD4-positive cells at the beginning of the treatment and HLA typing (de Maat[n 1] et al., Eur J Clin Pharmacol 2003; Kiertiburanakul et al., Curr HIV Res 2008). The current recommendation for initiation of NVP is for women with CD4<250 cells/mm3 and for men who has CD4<400 cells/mm3 when the indication for HAART fulfilled. (Baylor et al, 2004 and Sanne et al, 2005) In order to reduce the chance of hypersensitivity reaction, it was recommended that treatment should start with 200 mg single dose daily nevirapine for 14 days (lead-in), and followed by 200 mg twice daily. Monitoring of rash and hepatitis is recommended for the first three months.
Human Leukocyte Antigen is part of Major Histocompatibility Complex (MHC) on chromosome 6, the region covers 3.5 million base pairs, the HLA translated into a glycoprotein on the cell surface of immunology related cells and react to intruder antigens. HLA can be classified into three groups 1) Class I antigen (HLA-A, HLA-B and HLA-C). This class is attached to the exogenous antigens or drugs and introduce the foreign antigens to immune cells such as T lymphocyte. T lymphocyte can be stimulated and kill the cell invaded by drugs or foreign organisms. 2) Class II antigens (HLA-DR, HLA-DP and HLA-DQ) are the proteins that attached to endogenous protein and presented those protein to the B lymphocyte to produce antibody to the exogenous antigen. 3) Class III genes is the left over of the class I and class II, function in complement, hormone and intracellular peptide processing.
The hypersensitivity reactions of an antiretroviral drug, abacavir, had been extensively studied and its association to the HLA-B*5701 allele in Caucasians have been strongly implicated with odds ratios 117, negative predictive value more than 90% in every ethnic studies, but highly variable positive predictive value due to variability of HLA-B*5701 allele frequencies in each population. (Mallal et al., Lancet 2002; Hetherington et al., Lancet 2002; Martin et al., Proc Natl Acad Sci 2004).
Association study in hypersensitivity to nevirapine by Martin et al had reported that HLA-DRB1*0101 in patient with high CD4 level may determine susceptibility to nevirapine hepatitis with 40% positive predictive value and 96% negative predictive value (Martin et al., AIDS 2005). However this result had never been confirmed and no single HLA allele were associated with cutaneous adverse reactions from nevirapine in the study.